Many products are formed by coating a solvent-containing composition onto a suitable substrate. Such compositions generally include enough solvent so that the composition has a viscosity that allows the composition to be coated onto the substrate at a desired thickness using a desired coating technique. After coating the composition onto the substrate, it is often desirable to remove the solvent to dry the coating.
One drying technique involves heating the coated substrate in an oven to remove the solvent(s) by evaporation. Oven drying typically involves conveying large volumes of heated gas (e.g., air, an inert atmosphere, or the like) through the oven in order to heat and evaporate the solvent(s). As the stream of heated gas is conveyed through the oven, nearly all of the volatile components of the coated composition having a measurable vapor pressure at the drying temperature being used will tend to evaporate from the coating into the heated gas.
Evaporation of any particular volatile component occurs until the partial pressure of that component in the heated gas equals that component""s vapor pressure at the surface of the liquid coating, meaning that an equilibrium with respect to that component has been established. However, because of the large volume of heated gas in the chamber at any one time and the fact that fresh heated gas is continuously supplied to the oven during drying, an equilibrium is rarely reached between the heated gas and any volatile component of the coating. As a general consequence, all of the volatile components of the coating tend to continuously evaporate and be carried away in the stream of heated gas throughout the entire drying process.
Of course, when drying is controlled by gas phase mass transfer more volatile components of the coating will evaporate at a faster rate than less volatile components. Nonetheless, evaporation of all the volatile components still occurs even if the drying temperature is well below the boiling point of one or more of the volatile components. In other words, the amount of non-solvent, volatile ingredients in the resultant dried coating will be different, and substantially so in some instances, than the amount of non-solvent volatile ingredients in the initial wet coating. Thus, oven drying offers poor control over the component drying process, because more than just the solvent(s) may be removed from the coating.
The impact of oven drying upon the composition of a dried coating can be illustrated in connection with the manufacture of a transdermal drug delivery device, also known as a transdermal patch. A conventional xe2x80x9cpeel and placexe2x80x9d transdermal patch generally includes a drug-in-adhesive layer sandwiched between an impermeable backing and a release liner. At the time of use, the release liner is removed so that the patch can be attached to a patient, adhesive side down. Over time, the drug in the adhesive layer penetrates into the patient, or is topically active, in furtherance of the desired therapeutic treatment. Optionally, the drug-in-adhesive formulation may include one or more compounds known as penetration enhancers that increase the permeability of the patient""s tissue to the drug.
Transdermal patches may be manufactured by coating a suitable substrate (e.g., the release liner, the impermeable backing material, or adhesive coated web, as the case may be) with a coating composition that includes one or more pharmacologically active agents (the drug or drugs, as the case may be), a pressure sensitive adhesive, optionally one or more penetration enhancers, and optionally one or more other excipients. Typically, one or more solvents are also included in the coating composition to facilitate forming a homogeneous coating composition having a suitable coating viscosity. For purposes of illustration, the solvent and the penetration enhancer will be deemed to be the only volatile components of the coating composition, wherein the solvent is substantially more volatile than the penetration enhancer. After such a composition is coated, the solvent is removed to dry the coating. However, because both the solvent and penetration enhancer are volatile components, both the solvent and the penetration enhancer will evaporate upon drying. Thus, a portion of the penetration enhancer in the original formulation is lost during drying. This loss of some of the penetration enhancer during drying is particularly problematic since the drug in adhesive layer of a transdermal patch must often meet tight composition and performance specifications.
Although this discussion of the drug-in-adhesive layer has assumed that only the solvent and the penetration enhancer are volatile components of the coating composition, this might not always be the case. In actual practice, for instance, at least the solvent and any one or more other ingredients of the coating composition may be volatile components.
Knowing that drying often will remove more than just the solvent from a coating being dried, an original coating formulation can include extra amounts of any one or more volatile, non-solvent ingredients in an attempt to compensate for losses that might occur during drying. For example, if a specification requires five weight percent (on a solids basis) of a penetration enhancer in a transdermal patch, but it is known that approximately two weight percent (on a solids basis) of the penetration enhancer might be lost during drying, then the original coating formulation can be formulated with about seven weight percent (on a solids basis) of the penetration enhancer in order to compensate for drying losses. This technique of incorporating extra amounts of ingredients into a coating formulation to compensate for drying losses is often referred to as xe2x80x9cover formulationxe2x80x9d. Over formulation can result in significant cost increase in producing the final product due to the amount of excess materials lost during conventional drying practices.
Accordingly, what is needed is a more accurate approach for drying coatings so that the composition of the resultant dried coating meets precise specifications.
The present invention relates to a method of selectively removing volatile components from a coated composition. It has now been discovered that the gap drying technique can be used in order to selectively cause some volatile components (i.e., xe2x80x9cnonresidentxe2x80x9d volatile components) to be removed from a coating during drying without removing significant amounts of other volatile components (i.e., xe2x80x9cresidentxe2x80x9d volatile components). In many instances, nonresident ingredients will be the solvents incorporated into a coatable composition. Resident ingredients may be any other ingredients other than the solvent(s).
Gap drying generally involves positioning a coated substrate between a condensing surface and a heating surface. The coated surface of the substrate faces the condensing surface and is separated therefrom by a relatively small gap. The heating surface is in thermal contact with the other side of the coated substrate. The energy from the heating surface is transferred through the substrate to the coating and causes certain components to evaporate from the coating. The resultant vapor travels across the gap above the coating and condenses on the condensing surface. The condensate is collected and removed. Advantageously, the vapor may be condensed, collected, and removed continuously so that the partial pressure of the evaporated component(s) never reaches the corresponding vapor pressure that would be exhibited at steady state equilibrium. As a consequence, the component to be removed from the coating can be continuously evaporated until substantially none of the component remains in the coating.
It has now been discovered that the gap drying process can be used to selectively remove one or more specific volatile components from a coated composition while substantially all of one or more other volatile components remain in the composition. The present invention is able to adapt the gap drying approach to selectively volatilize some components, but not others. This approach is different from conventional convective oven drying carried out at the same heating temperature, because convective oven drying does not selectively volatilize components with the kind of precision provided by gap drying. Gap drying has been described in more detail in U.S. Pat. No. 5,581,905 (Huelsman), U.S. Pat. No. 5,980,697 (Kolb) and U.S. Pat. No. 5,694,701 (Huelsman), incorporated herein by reference in their respective entireties.
Advantageously, selective gap drying in accordance with the present invention allows dried coatings with precise compositions to be formed, because selective gap drying substantially reduces the need to over formulate in order to meet target composition specifications. Except for the solvent(s), the composition to be coated can be formulated at the outset to match the target composition of the dried coating. This ability to precisely match and then maintain the target coating composition is particularly beneficial in connection with the manufacture of transdermal drug delivery compositions which are subject to stringent specifications.
As a concrete example of how the present invention offers improved precision when preparing transdermal drug delivery compositions containing one or more volatile ingredients, the advantages of the present invention may be highlighted in connection with a representative transdermal delivery device suitable for the transdermal delivery of testosterone. Such a device might have a drug-in-adhesive layer whose specification, for purposes of illustration, requires 6 parts by weight testosterone, 23 parts by weight terpineol (boiling point in the range of 214xc2x0 C. to 224xc2x0 C.), 2 parts by weight lauramine oxide, and 69 parts by weight of a pressure sensitive adhesive, based upon 100 parts by weight of the dried coating. The specification might further recite that this layer is to be applied from a coating formulation including a solvent of 239.4 parts by weight of ethyl acetate (boiling point of 77xc2x0 C.) and 26.6 parts of methanol (boiling point of 64.5xc2x0 C. ) per 6 parts by weight of testosterone. In this particular coating formulation, the terpineol (used as a penetration enhancer), the ethyl acetate (a solvent), and the methanol (a solvent) would be the volatile constituents.
Ordinarily, the above coating formulation might be coated onto a substrate and then dried in an oven in order to remove the solvents, i.e., the ethyl acetate and the methanol. Unfortunately, conventional oven drying would remove not just the solvents, but also substantial portions of the terpineol as well. For example, in order to end up with a dried coating having the specified 23 parts by weight of terpineol when using conventional oven drying, it might be necessary to include as much as 100% more terpineol in order to hit the terpineol target. In other words, 50% of the terpineol included in the original coating formulation is lost during conventional oven drying. Conventionally, the original coating formulation would be over formulated, to compensate for this drying loss. This terpineol loss occurs even if oven drying is carried out at a temperature well below the boiling point of the terpineol, e.g., as low as 66xc2x0 C.
In contrast, when using selective gap drying according to the present invention, the solvents can be selectively removed from the coating with substantially little impact upon the terpineol content of the coating as the coating dries. For example, if the dried coating is to include 23 parts by weight of terpineol per 6 parts by weight testosterone, then the coating composition may also be formulated with precisely this amount of terpineol. Little (perhaps up to approximately an extra 2% most typically) to no over formulation of terpineol is required because the solvent is selectively removed.
Consequently, the original coating composition (not including solvent) can be formulated at the outset to match the desired dried coating composition. With oven drying, the non-selectivity of the removal of volatile components causes over-formulation in order to compensate for the undesirable loss of material. The utilization of gap drying and the selectivity afforded by the process eliminates over-formulation. Thus the formulator does not have to empirically determine how much terpineol might be lost during oven drying. Dried coatings having target compositions can be formed with great precision as a result.
In one aspect, the present invention relates to a method of selectively removing volatile components from a composition, comprising coating an admixture onto a first substrate surface of a substrate, wherein the admixture comprises one or more volatile solvents, one or more volatile ingredients selected from the group consisting of liquid drugs, liquid excipients and mixtures thereof, and if the volatile ingredient is not therapeutically active, one or more drugs. The method further comprises the step of positioning at least a portion of the coated substrate between a condensing surface having a condensing surface temperature and a heating surface having a heating surface temperature that is greater than the condensing surface temperature, wherein the condensing surface is in a spaced apart, confronting relationship to the coated surface of the substrate and wherein the heated surface is in thermal contact with a second substrate surface opposite the first substrate surface. In the method, the heated surface temperature and the condensing surface temperature are such that the positioning step causes the solvent(s) to be selectively removed from the portion of the coated substrate while substantially all of the volatile ingredient(s) remains in the coated admixture to form the transdermal drug delivery composition.